PROJECT SUMMARY More than 10,000 patients are diagnosed each year with glioblastoma, the most common primary brain tumor. Current treatments are inadequate and there have been no major therapeutic breakthroughs in decades. Hence, there is an urgent need to develop novel strategies to address this devastating disease. However, development of an effective treatment for glioblastoma is severely hampered by 1) the blood-brain barrier (BBB), 2) an infiltrative growth pattern, 3) rapid development of therapeutic resistance, and, in many cases, 4) dose-limiting toxicity due to systemic exposure. To overcome these challenges, OncoSynergy, Inc. in collaboration with Dr. Balveen Kaur (University of Texas-Houston) is developing a novel therapeutic delivery approach to address each of these hurdles. This approach consists of a herpes simplex virus type 1-based oncolytic virus (HSV) that expresses an anti-CD29 (aCD29) antibody fragment and intracranial administration to the tumor and/or tumor infiltrated brain (TIB) via convection-enhanced delivery (CED). Many HSV vectors have been generated and are currently being tested at different stages in clinical trials for glioblastoma. However, complete responses or therapeutic efficacy have rarely been observed, indicating significant improvements in HSV therapy are necessary. Remarkably, our recent study showed that CD29 blockade using OS2966, a humanized anti-CD29 monoclonal antibody, enhances the efficacy of HSV in an orthotopic xenograft model of glioblastoma. Specifically, OS2966 treatment decreases interferon signaling and pro- inflammatory cytokine induction in HSV-treated tumor cells and inhibits migration of macrophages, resulting in enhanced HSV replication and cytotoxicity. Intratumoral OS2966 treatment also significantly enhances HSV replication and HSV-mediated anti-tumor efficacy in orthotopic xenograft model of glioblastoma. Importantly, OS2966 is FDA Orphan Drug designated in the treatment of glioblastoma and, in March, 2019, OncoSynergy has received IND clearance of OS2966 by the FDA as a monotherapy in recurrent glioblastoma (IND 139483). Hence, logically extend our studies, we propose to develop a novel HSV-mediated delivery system (i.e., HSV encoding a fragment of OS2966, which will be secreted outside viral infected tumor cells) to precisely enhance the synergistic effects of HSV and CD29 blockade. We will engineer an HSV encoding a fragment of OS2966 (HSV-aCD29) and determine in vitro and in vivo efficacy of HSV-aCD29. The successful completion of this Phase I STTR project will result in the generation of a multimodal therapeutic approach empowered by a novel HSV-mediated drug delivery system for the treatment of glioblastoma. Building on this milestone, our Phase II STTR project will further optimize this novel treatment regime in preclinical glioblastoma models and pursue IND-enabling studies to support IND submission.